Methods of ortho alkylation

ABSTRACT

The present invention pertains to methods for preparing a compound of Formula (I), wherein A is O or N-L; each L is independently H or an acyl group; K is, together with the two contiguous linking carbon atoms, a phenyl ring, a 5- or 6-membered heteroaromatic ring or an aromatic 8-, 9- or 10-membered fused carbobicyclic or heterobicyclic ring system wherein each ring or ring system is optionally substituted; R 1  is H, C 1  to C 4  alkyl or CO 2 R 3 ; R 2  is H or C 1  to C 4  alkyl; and R 3  is C 1  to C 4  alkyl; comprising hydrogenating a compound of Formula (II), wherein n is 0, 1 or 2 in the presence of a catalyst comprising palladium to form the compound of Formula (I). This invention further pertains to methods for preparing compounds of Formula (II) useful for preparing compounds of Formula (I). This invention also pertains to compounds used in these methods

REFERENCE TO RELATED APPLICATIONS

This application is a national filing under 35 U.S.C. 371 ofInternational Application No. PCT/US02/07880, filed 14 Mar. 2002, whichclaims priority benefit of Provisional Application 60/275,566, filed 14Mar. 2001.

FIELD OF THE INVENTION

The present invention pertains to improved methods for the preparationof ortho alkylated aromatic alcohols and amines.

BACKGROUND OF THE INVENTION

Orthoalkylated anilines and phenols are important building blocks in thepreparation of plant protection agents, pharmaceuticals and other finechemicals. Classical Friedel-Crafts alkylation of anilines and phenolstypically leads to para as well as ortho alkylation, and furthermoreoften results in polyalkylation. While Friedel-Crafts acylation ofanilines and phenols typically gives only monosubstitution, substitutionstill can occur at the para as well as ortho positions, and reactionconditions needed for reductive removal of the acyl carbonyl moiety maybe incompatible with other functionality on the molecule.

In the 1970s, Paul Gassman led the development of an alternativesynthetic method affording regioselective orthoalkylation (for leadreferences see P. G. Gassman and G. Gruetzmacher, J. Am. Chem. Soc.1973, 95, 588–589; P. G. Gassman and G. Gruetzmacher, Org. Syn., Coll.Vol. VI, 581–583; P. G. Gassman and H. R. Drewes, J. Am. Chem. Soc.1978, 100, 7600–7610; P. G. Gassman and D. R. Amick, J. Am. Chem. Soc.1978, 100, 7611–7619). The Gassman method involves generating anintermediate species believed to have the Formula i from the aniline orphenol and an alkyl thioether such as dimethyl sulfide and oxidizingagents such as tert-butyl hypochlorite or chlorine.

wherein A is NH or O, and (R)_(p) denotes optional substituents.

Treatment with base such as triethylamine or sodium methoxide effectsrearrangement to give an ortho alkylthioalkyl compound illustrated byFormula ii.

wherein A is NH or O, and (R)_(p) denotes optional substituents.

Lastly, desulfurization treatment with Raney nickel cleaves thealkylthioalkyl group to an alkyl group as illustrated by Formula iii.

wherein A is NH or O, and (R)_(p) denotes optional substituents.

While this method offers an attractive alternative to Friedel-Craftsmethods of aromatic alkylation, its conditions are not ideal forpreparation on an industrial scale. Particularly disadvantageous is itsuse of Raney nickel to cleave the alkylthioalkyl group to alkyl. Raneynickel is used as a reagent instead of a true catalyst and thus isexpensive. Moreover, it is pyrophoric and must be kept covered withwater. Although slurrying the spent material in water and flushing downthe drain is suggested by P. G. Gassman, G. Gruetzmacher, Org. Syn.,Coll. Vol. VI, 581–583, this article recognizes such disposal to beenvironmentally unsound. A more satisfactory alternative to Raney nickelis needed for industrial manufacture using this method.

Another disadvantage of this method is that the procedures used toprepare species illustrated by Formula i often rely upon coldtemperatures, as low as −50° C. As refrigeration is expensive, the needto maintain such low temperatures is undesirable in industrialmanufacture of chemicals.

A. D. Dawson and D. Swern (J. Org. Chem. 1977, 42, 592–597) reportpreparation and isolation of the species illustrated by Formula i bytreatment of anilines with dimethyl sulfide activated byN-chlorosuccinimide or N-chlorobenzotriazole, again at low temperatures.This reference does not disclose rearrangement to compounds illustratedby Formula ii. U.S. Pat. No. 4,496,765 discloses preparation of an ylidof Formula iv by washing with aqueous sodium hydroxide solution adichloromethane solution of the corresponding compound of Formula i,which is formed from 2-(trifluoromethyl)-aniline, dimethyl sulfide andN-chlorosuccinimide.

wherein (R)_(p) denotes optional substituents.

U.S. Pat. No. 4,496,765 also discloses preparation of a compound ofFormula ii by heating the ylid of Formula iv, optionally in the presenceof catalytic succinimide.

P. Claus and W. Vycudilik (Tetrahedron Lett. 1968, 3607–3610; Monatsch.Chem. 1970, 101, 396–404) report that anilines can be transformed intoreadily isolable ylids illustrated by Formula iv by treatment withdimethyl sulfoxide, phosphorus pentoxide and triethylamine in chloroformat temperatures near room temperature. In this reaction, thetriethylamine base may be presumed to deprotonate an intermediatespecies illustrated by Formula i. The intermediate ylids illustrated byFormula iv are then reported to rearrange to ortho alkylthioalkylcompounds illustrated by Formula ii in the presence of bases such astriethylamine or in protic solvents such as alcohols and water evenwithout the addition of base (see also P. Claus and W. Rieder, Monatsh.Chem. 1972, 103, 1163–1177). As this method avoids need for lowtemperatures, it is industrially more attractive, but the cost ofphosphorus pentoxide and disposing of phosphorus wastes would be ofconcern industrially. These references do not address thedesulfurization conversion of Formula ii to Formula iii.

Because of potentially lower cost and easier treatment of waste, sulfurtrioxide is more industrially attractive than phosphorus pentoxide. U.S.Pat. No. 3,527,810 discloses a process for preparing the sulfur trioxidecomplex with dimethyl sulfoxide, and T. E. Varkey, G. F. Whitfield andD. Swem (J. Org. Chem. 1974, 39, 3365–3372) report the use of sulfurtrioxide to activate dimethyl sulfoxide in reaction with aromatic aminesto form ylids illustrated by Formula iv after treatment with base. Forthe reaction of the sulfur trioxide complex of dimethyl sulfoxide withp-toluenesulfonamide, this reference reports cosolvents such aschloroform giving lower yields. For the reaction of the sulfur trioxidecomplex of dimethyl sulfoxide with aromatic amines, this referenceavoids a cosolvent and teaches a ratio of DMSO:SO₃: aromatic amine of4–6:1:0.6–0.9, and recommends this over a DMSO:SO₃ ratio of 2–3:1. Thisreference also describes use of acetic anhydride, trifluoroaceticanhydride, trifluoromethanesulfonic anhydride, cyclohexylcarbodiimideand phosphorus pentoxide as activating agents for dimethyl sulfoxide.The reference does not report rearrangement of the ylids from aromaticamines.

None of the above references disclose useful alternatives to Raneynickel for the desulfurization conversion of Formula ii to Formula iiirequired by this method. U.S. Pat. Nos. 4,404,069 and 4,806,687 disclosesuch alternatives.

U.S. Pat. No. 4,404,069 uses electrolytic desulfurization to reduce2-(methylthio-methyl)-6-(trifluoromethyl)aniline or its correspondingsulfoxide or sulfone to 2-methyl-6-(trifluoromethyl)aniline. This methodrequires use of large amounts of quaternary ammonium salt electrolytesin addition to polar solvents, in which organic substances may not behighly soluble. U.S. Pat. No. 4,404,069 reports that sulfoxides andsulfones are more easily reduced than sulfides. Oxidation of sulfides tosulfoxides or sulfones requires an additional step. An undesirablepotential side reaction is reduction of halogen substituents. To avoidreduction of trifluoromethyl to difluoromethyl, U.S. Pat. No. 4,404,069recommends stopping the reaction before conversions exceed 85–90% orcontinuously extracting the product from the polar reaction mixture,which may also be needed to prevent phase separation of the reactant andproduct from the polar reaction medium.

U.S. Pat. No. 4,806,687 uses hydrodesulfurization with a presulfidedcobalt-molybdenum catalyst to reduce2-(methylthiomethyl)-6-(trifluoromethyl)aniline to2-methyl-6-(trifluoromethyl)aniline. The preferred temperature for thisreaction is 150 to 250° C. Moreover, a hydrogen pressure of more than3400 kPa is preferred to obtain practical reaction rates.

In view of the process requirements and limitations of these methods,further improvements are still needed to effect the desulfurizationconversion of Formula ii to Formula iii. Such an improvement has nowbeen discovered.

SUMMARY OF THE INVENTION

The present invention pertains to a method for preparing a compound ofFormula I

wherein

-   -   A is O or N-L;    -   each L is independently H or an acyl group;    -   K is, together with the two contiguous linking carbon atoms, a        phenyl ring, a 5- or 6-membered heteroaromatic ring or an        aromatic 8-, 9- or 10-membered fused carbobicyclic or        heterobicyclic ring system wherein each ring or ring system is        optionally substituted;    -   R¹ is H, C₁ to C₄ alkyl or CO₂R³;    -   R² is H or C₁ to C₄ alkyl; and    -   R³ is C₁ to C₄ alkyl;        comprising hydrogenating a compound of Formula II

wherein n is 0, 1 or 2; R⁴ is CHR¹R²; and A, K, L, R¹, R² and R³ are asdefined for Formula I, in the presence of a catalyst comprisingpalladium to form a compound of Formula I.

The present invention further pertains to aforesaid method wherein A isN-L in Formula I and further comprising before the hydrogenation step

-   (a) contacting a compound of Formula III,

-    wherein A is NH and K is as defined for Formula I, with a compound    of Formula IV    R¹R²CHS(O)R⁴  IV-    wherein R⁴ is CHR¹R² and R¹ and R² are as defined for Formula I, in    the presence of an activating agent and adding a base at the same    time or subsequently to the contact to form a compound of Formula V

-    wherein K, R¹ and R² are defined for Formula I and R⁴ is CHR¹R²;-   (b) rearranging the compound of Formula V to form a compound of    Formula II wherein A is N-L, each L is H and n is 0;-   (c) optionally acylating the compound of Formula II wherein each L    is H to form a compound of Formula II wherein at least one L is an    acyl group; and-   (d) optionally oxidizing the compound of Formula II wherein n is 0    to form a compound of Formula II wherein n is 1 or 2.

In particular, this invention pertains to a method for preparing acompound of Formula V

wherein

-   -   K is, together with the two contiguous linking carbon atoms, a        phenyl ring, a 5- or 6-membered heteroaromatic ring or an        aromatic 8-, 9- or 10-membered fused carbobicyclic or        heterobicyclic ring system wherein each ring or ring system is        optionally substituted;    -   R¹ is H, C₁ to C₄ alkyl or CO₂R³;    -   R² is H or C₁ to C₄ alkyl;    -   R³ is C₁ to C₄ alkyl; and    -   R⁴ is CHR¹R²;        the method comprising

-   (a) contacting a compound of Formula III,

-    wherein A is NH and K is as defined for Formula V, with a compound    of Formula IV    R¹R²CHS(O)R⁴  IV-    wherein R⁴ is CHR¹R²and R¹ and R² are as defined for Formula V, in    an inert solvent and in the presence of sulfur trioxide as an    activating agent to form a reaction product, and washing the    reaction product in the inert solvent with an aqueous solution of a    base to form the compound of Formula V.

This invention further relates to a method for preparing a compound ofFormula II

wherein

-   -   n is 0;    -   A is NH;    -   L is H;    -   K is, together with the two contiguous linking carbon atoms, a        phenyl ring, a 5- or 6-membered heteroaromatic ring or an        aromatic 8-, 9- or 10-membered fused carbobicyclic or        heterobicyclic ring system wherein each ring or ring system is        optionally substituted;    -   R¹ is H, C₁ to C₄ alkyl or CO₂R³;    -   R² is H or C₁ to C₄ alkyl;    -   R³ is C₁ to C₄ alkyl; and    -   R⁴ is CHR¹R²;        comprising the method described immediately above and a        subsequent step of rearranging the compound of Formula V in a        solvent to give the compound of Formula II.

This invention also pertains to novel compounds of Formulae I, II and Vuseful in these processes, such asS,S-dimethyl-N-[4-(trifluoromethyl)phenyl]sulfilimine,2-[(methylthio)methyl]-4-(trifluoromethyl)benzenamine, and2-[(methylsulfinyl)-methyl]-4-(trifluoromethyl)benzenamine.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkyl”, used either alone or in compound words such as“alkylaryl” includes straight-chain or branched alkyl, such as methyl,ethyl, propyl, i-propyl, or the different butyl, pentyl or hexylisomers. “Alkoxy” includes, for example, methoxy, ethoxy, propyloxy,isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.

The term “halogen”, either alone or in compound words such as“haloalkyl”, includes fluorine, chlorine, bromine or iodine, withfluorine and chlorine preferred for the process of this invention.

As used herein, the term “aryl” refers to an aromatic ring system or aradical derived therefrom. The term “aromatic ring system” denotes fullyunsaturated carbocycles and heterocycles in which the cyclic ring systemis aromatic (where aromatic indicates that the Hückel rule is satisfiedfor the ring system). The term “aromatic carbobicyclic ring system”includes ring systems in which all ring members are carbon atoms andincludes fully aromatic ring systems and ring systems in which at leastone ring of a polycyclic ring system is aromatic (where aromaticindicates that the Hückel rule is satisfied). The term “heterocyclicring” or “heterobicyclic ring system” denotes rings or ring systems inwhich at least one ring atom is not carbon and comprises 1 to 4heteroatoms independently selected from the group consisting ofnitrogen, oxygen and sulfur, provided that each heterocyclic ringcontains no more than 4 nitrogens, no more than 2 oxygens and no morethan 2 sulfurs. The heterocyclic ring can be attached through anyavailable carbon or nitrogen by replacement of hydrogen on said carbonor nitrogen. The term “aromatic heterobicyclic ring system” includesfully aromatic heterocycles and heterocycles in which at least one ringof a polycyclic ring system is aromatic (where aromatic indicates thatthe Hückel rule is satisfied). Examples of suitable groups for K linkedwith the two contiguous carbon atoms are groups containing aromatic andheteroaromatic five and six-membered rings such as benzene, thiophene,pyridine, pyridazine, pyrazine, pyrimidine, triazine, triazole, pyrrole,imidazole, pyrazole, furan, oxazole, isoxazole, thiazole, thiadiazole,oxathiazole and polycyclic rings comprising combinations of themononuclear aromatic structures, such as naphthalene, benzo[b]thiophene,benzofuran, quinoline, isoquinoline, quinoxaline, indole, isoindole,naphthyridine, indazole, benzopyrrole, benzotriazole, benzimidazole,benzoxazole, benzothiadiazole, and benzisothiazole. Additionally,bicyclic structures may be included, where one of the rings is aromaticand the other saturated. Examples include such compounds as1,2,3,4-tetrahydronapthalene, dihydroindole, dihydroisoindole anddihydrobenzopyran. An enormous variety of these aryl ring systemssuitable for the process of the present invention, and methods forpreparation of these aryl ring systems are well known in the art. For anextensive review see: Comprehensive Organic Chemistry, D. Barton and W.D. Ollis eds., Pergamon Press, NY, 1979, Volumes 1–6; ComprehensiveHeterocyclic Chemistry, A. R. Katritzky and C. W. Rees eds., PergamonPress, NY, 1984, Volumes 1–8; Comprehensive Heterocyclic Chemistry II,A. R. Katritzky, C. W. Rees and E. F. V. Scriven eds., Pergamon Press,NY, 1996, Volumes 1A–11; and the references cited therein.

Suitable substituents on the aryl group are those moieties that are notreducible under the palladium-catalyzed hydrogenation reactionconditions, which are understood by one skilled in the art. For a reviewof the susceptibility of organic groups to hydrogenation, see P. N.Rylander, Catalytic Hydrogenation in Organic Syntheses, Academic Press,NY, 1979 and M. Freifelder, Catalytic Hydrogenation in Organic SynthesisProcedures and Commentary, John Wiley & Sons, NY, 1978. For example,substituent groups resistant to these hydrogenation reaction conditionsinclude such halogens as fluorine and chlorine; straight chain, branchedand cycloalkyl groups; straight chain and branched alkoxy groups;straight chain and branched haloalkyl groups; straight chain andbranched haloalkoxy groups; aryloxy groups (which can contain additionalsubstituents such as alkyl) such as phenoxy; carboxylic acid groups;cyano groups; aryl and arylalkyl groups groups (which can containadditional substituents such as alkyl), for example, 4-methylbenzyl or4-ethylpyridinyl.

Preferred are:

-   -   Preferred 1: Methods and compounds of this invention wherein A        is other than O.    -   Preferred 2: Methods and compounds of this invention wherein R¹        is H or CO₂CH₃, R² is H and R⁴ is CH₃ or CH₂CO₂CH₃.    -   Preferred 3: Methods and compounds of this invention wherein R¹        and R² are H.    -   Preferred 4: Methods and compounds of this invention wherein K,        together with the two continguous carbon atoms is optionally        substituted with one or more groups independently selected from        halogen, C₁–C₄ alkyl, C₁–C₄ alkoxy, C₁–C₄ haloalkyl and C₁–C₄        haloalkoxy.    -   Preferred 5: Methods and compounds of this invention wherein K,        together with the two contiguous carbon atoms, is a phenyl ring        optionally substituted with one or more groups independently        selected from halogen, C₁–C₄ alkyl, C₁–C₄ alkoxy, C₁–C₄        haloalkyl, C₁–C₄ haloalkoxy, phenyl and phenoxy, each phenyl or        phenoxy group optionally substituted with one or more groups        independently selected from halogen, C₁–C₄ alkyl, C₁–C₄ alkoxy,        C₁–C₄ haloalkyl and C₁–C₄ haloalkoxy.    -   Preferred 6: Methods and compounds of this invention wherein K,        together with the two contiguous carbon atoms, is a phenyl ring        optionally substituted with one or more groups independently        selected from halogen, C₁–C₄ alkyl, C₁–C₄ alkoxy, C₁–C₄        haloalkyl and C₁–C₄ haloalkoxy.    -   Preferred 7: Methods and compounds of Preferred 6 wherein the        phenyl ring is substituted with halogen, C₁–C₄ alkyl, C₁–C₄        alkoxy, C₁–C₄ haloalkyl or C₁–C₄ haloalkoxy para to A.

As shown in Scheme 1, ortho alkylated aromatic alcohols and amines, andtheir acylated derivatives, of Formula I can be prepared from compoundsof Formula II.

wherein

-   -   n is 0, 1 or 2;    -   A is O or N-L;    -   each L is independently H or an acyl group;    -   K is, together with the two contiguous linking carbon atoms, a        phenyl ring, a 5- or 6-membered heteroaromatic ring or an        aromatic 8-, 9- or 10-membered fused carbobicyclic or        heterobicyclic ring system wherein each ring or ring system is        optionally substituted;    -   R¹ is H, C₁ to C₄ alkyl or CO₂R³;    -   R² is H or C₁ to C₄ alkyl;    -   R³ is C₁ to C₄ alkyl; and    -   R⁴ is CHR¹R².

In Formulae I and II, an acyl group as specified for L is understood tobe a group linked by carbonyl, i.e. C(O)—R^(a). R^(a) can, in turn, beany group compatible with hydrogenation conditions, for example, H, C₁to C₄ alkyl, CF₃, C₁ to C₄ alkoxy or C₁ to C₄ haloalkoxy. Each R^(a) isselected independently for each occurrence of L.

The transformation shown in Scheme 1 can be achieved by the use of acatalyst comprising palladium in the presence of hydrogen. Preferablythe catalyst comprises tin in addition to the palladium to resistpoisoning by sulfur. The active portion of the catalyst can containpalladium and optionally tin alone, or it can further comprise othermaterials to enhance performance. A catalyst comprising tin from about5% to about 20% of the weight of the palladium is preferred. (Thismeans, for example, if 1000 mg of palladium is present then the amountof tin ranges from about 50 mg to about 200 mg.) More preferably, thetin content is from about 8% to about 12% of the weight of thepalladium.

The catalyst employed in the present invention is preferably supportedon a carrier, most preferably a carrier having a high specific surfacearea Such carriers include, for example, activated charcoal or carbon,silica gel, alumina or magnesia. Preferably the carrier is a porousparticulate solid with a size distribution typically ranging from 5 to100 μm for slurry applications and from about 0.8 to 4 mm for fixed bedapplications and a BET (Brunauer-Emmett-Teller method) surface areatypically ranging from about 300 to nearly 2000 m²/g. The catalystcarrier can be manufactured such as to have a latent acid, neutral orbasic pH. Optionally the catalyst carrier can be treated prior to metaldeposition by one or more techniques generally known in the art, such asimpregnation with alkali metal salts and/or calcination or acid wash.Preferably the catalyst carrier is an activated charcoal or carbonsupport. Preferably the activated charcoal or carbon support has anaverage particle size on the order of 20 μm for slurry applications and3 mm for fixed bed applications and a BET surface area from about 700 toabout 1600 m²/g.

Palladium catalysts are typically prepared by contacting a palladiumcompound such as palladium(II) chloride with a reducing agent. Byincluding a tin compound such as tin(II) chloride or tin(IV) chloridewith the palladium compound, reduction provides a catalytic mixture ofpalladium and tin.

To prepare a palladium catalyst on a carrier, a standard method is toprepare a water solution of a soluble palladium compound such aspalladium(II) chloride, preferably also containing hydrochloric acid,and add this solution to the carrier. The water is then evaporated todeposit the palladium compound in the carrier matrix. The solution canbe added to the carrier by any technique generally known in the art,including by example but not limitation, immersion, spraying or thelike. The dry or partially dry composite material is then contacted witha reducing agent for a period of time sufficient to reduce thepalladium. Such procedures are described by R. Mozingo in OrganicSyntheses, Collective Volume 3, Wiley, New York, 1955, pages 685–690.

To include tin in the palladium catalyst on a carrier, the above methodcan be modified to include a soluble tin compound, such as tin(II)chloride or tin(IV) chloride, in the solution of the soluble palladiumcompound before application to the carrier. Alternatively, separatesolutions of the soluble palladium and soluble tin compounds can beprepared and sequentially applied to the carrier.

Optionally the catalyst precursor can be added to the hydrogenationreactor for the process of Scheme 1 wherein the reduction of palladiumand tin occurs in situ in the hydrogenation reactor. Preferably thecatalyst is prereduced with a reducing agent before use.

Alternative methods for preparing a palladium catalyst supported on acarrier include contacting with a reducing agent a mixture comprisingsuspended carrier and a solution of a soluble palladium optionallycontaining a soluble tin compound. Another method of preparing asupported palladium-tin catalyst involves evaporating a solution of apalladium compound onto the carrier and then applying vapor of avolatile tin compound, such as tin(IV) tetrachloride, to the carrierbefore contact with a reducing agent. Furthermore various other methodsor alternate modes are possible for depositing the palladium and/or tincompounds on a carrier, such as by selective precipitation or the like,optionally with or without solvent washing such as to selectively removeless desired counterions.

As an alternative to applying the palladium and optional tin compoundsto the carrier and then reducing, the carrier can be first impregnatedwith a reducing agent and then the palladium and optional tin compoundsapplied to the carrier. The residual reducing agent can then be washedor otherwise removed from the carrier. This method can preferentiallydeposit the metals near the surface of the carrier particles.

For preparing the catalyst, any palladium compound can be used that iswater soluble. This includes by way of example, but not limitation,palladium(II) acetate, palladium(II) acetylacetonate, palladium(II)bromide and palladium(II) chloride. Palladium(II) chloride is generallypreferred.

Tin compounds useful for preparing the catalyst include those that arewater soluble or sufficiently volatile to enable vapor-phase depositionon a carrier. These include tin(II) chloride, tin(IV) chloride, tin(II)oxalate, tin(II) nitrate, sodium stannate and the like. Typicallytin(II) chloride and tin(IV) chloride are used because of readyavailability.

The reducing agent employed to chemically reduce the palladium andoptionally tin can generally be any reductant or reducing environmentconsistent with either liquid phase reduction or vapor phase reduction,including by way of example, but not limitation, formaldehyde, sodiumformate, glucose, acetaldehyde, sodium borohydride, hydrogen and thelike. Reduction using hydrogen gas is a preferred method of reduction.Reduction using hydrogen gas can be conducted using a suspension of thesolid catalyst precursor in a hydrogenation solvent such as ethylacetate, tetrahydrofuran, toluene, acetic acid or acetic anhydride. Whena solvent is employed using hydrogen gas, the temperature range isgenerally between ambient and 200° C. (preferably 50 to 150° C.), andthe pressure is generally between atmospheric pressure and 20000 kPa.Preferably the reduction using hydrogen gas is conducted without solventusing a vapor phase comprising gaseous hydrogen with or without an inertgas such as nitrogen or the like in the presence of the solid catalystprecursor; generally such a vapor phase reduction is performed at atemperature range between ambient and 500° C. (preferably 100 to 300°C., most preferably 150 to 250° C.) at atmospheric pressure or up to apressure of 20000 kPa.

Palladium catalysts including those containing tin are produced byEngelhard Corporation, Chemical Catalysts, Process Technologies Group,101 Wood Avenue, Iselin, N.J. 08830-0770 U.S.A.

The reaction of Scheme 1 is usually conducted at pressures of 10² to 10⁴kPa (14.5 to 1450 psi) in a suitable organic solvent such as, but notlimited to, ethyl acetate, tetrahydrofuran, toluene, acetic acid oracetic anhydride. Hydrogen pressures of around 1000 kPa generallyachieve convenient rates of reaction. Elevated temperatures of 80 to200° C. are usually required to achieve the transformation.

Shown in Scheme 1a is an illustrative subgenus of the transformation ofScheme 1 wherein K is, together with the two contiguous linking carbonatoms, an optionally substituted phenyl ring.

wherein n is 0, 1 or 2; A is O or N-L; each L is independently H or anacyl group C(O)—R^(a); each R^(a) is independently selected, forexample, from H, C₁ to C₄ alkyl, CF₃, C₁ to C₄ alkoxy and C₁ to C₄haloalkoxy; m is 0 to 4; and each R⁵ is independently selected fromhalogen, C₁–C₄ alkyl, C₁–C₄ alkoxy, C₁–C₄ haloalkyl, C₁–C₄ haloalkoxy,phenyl or phenoxy, each phenyl or phenoxy group optionally substitutedwith groups independently selected from halogen, C₁–C₄ alkyl, C₁–C₄alkoxy, C₁–C₄ haloalkyl and C₁–C₄ haloalkoxy.

As already mentioned, in the method of Schemes 1 and 1a, L can be H oran acyl group C(O)—R^(a) wherein R^(a) can be any group stable tohydrogenation such as H, C₁ to C₄ alkyl, CF₃, C₁ to C₄ alkoxy and C₁ toC₄ haloalkoxy. Because of the low cost of acetic anhydride, R^(a) beingmethyl is preferred. As unacylated amino groups can potentially poisoncatalysts, acylating them can facilitate the method of Schemes 1 and 1a.Amino (i.e. A-L is NH₂) or hydroxy (i.e. A-L is OH) functions ofFormulae II and IIa can be converted to acylated derivatives beforecontacting with hydrogen and catalyst, or as discussed below, acylationcan be conducted in situ if the hydrogenation solvent comprises an acidanhydride.

A variety of methods for acylating amino and hydroxy functions are wellknown to those skilled in the art. Generally the process of acylatingthe A-L group of a compound of Formula II or IIa wherein A-L is OH orNH₂ involves contacting the compound with an acylating agent. Typicalacylating agents are the corresponding acid halides, particularlychlorides (e.g., Cl—C(O)—R^(a)), and acid anhydrides (e.g.,R^(a)—C(O)OC(O)—R^(a)). Acid anhydrides are more commonly used whenR^(a) is H or a carbon-linked group such as C₁ to C₄ alkyl and CF₃. Whenthe desired acyl function is formyl (i.e., R^(a) is H), the mixedanhydride H—C(O)OC(O)—CH₃ is particularly useful as the acylating agent.Acid halides are most useful as acylating agents when R^(a) is otherthan H, for example, C₁ to C₄ alkyl, CF₃, C₁ to C₄ alkoxy and C₁ to C₄haloalkoxy. Often the acylating reaction is conducted in a solvent inertto the acylating agent, such as dichloromethane, tetrahydrofuran ortoluene. However, particularly with inexpensive acid anhydride acylatingagents, such as acetic anhydride, it may be convenient to use theacylating agent as the solvent. As the acylating reaction generates anacid byproduct (carboxylic acids, e.g., HO—C(O)—R^(a), from acidanhydride acylating agents, and hydrogen halides, e.g., HCl, from acidhalide acylating agents), the reaction is often conducted in thepresence of a base, particularly with acid halide acylating agents.Suitable bases can include tertiary amines such as triethylamine,diisopropylethylamine and the like, and inorganic bases such as alkaliand alkaline earth metal carbonates. The acylation reaction can beperformed in the presence of acylation catalysts, such as4-(dimethylamino)pyridine. The acylation reaction is often conductednear ambient temperature, but can be conducted over a wide range oftemperatures, such as between 0° C. and the boiling point of thesolvent. The acylated product (i.e. Formula II or IIa wherein at leastone L is an acyl group) can be isolated and purified by conventionalmeans, such as evaporation of solvent, crystallization, chromatography,etc. For general procedures useful for acylating compounds of Formula IIor IIa wherein A-L is OH or NH₂ see pp. 101–107 and pp. 223–266,respectively, of T. W. Greene, Protective Groups in Organic Synthesis,Wiley-Interscience, New York, 1981 and the references cited therein.This reference also describes methods of deacylating compounds to formfree hydroxy and amino groups.

As already mentioned, even if each L in Formula II is H, the use ofacetic or another acid anhydride as hydrogenation solvent can result inthe acylated derivatives of Formula I. For example, in the reaction ofScheme 1a when each L in Formula IIa is H, use of acetic anhydride assolvent can produce acylated derivatives of Formula VIa when A is O andacylated derivatives of Formula VIb and diacylated aniline derivativesof Formula VIc when A is NH.

wherein m is 0 to 4; and each R⁵ is independently selected from halogen,C₁–C₄ alkyl, C₁–C₄ alkoxy, C₁–C₄ haloalkyl, C₁–C₄ haloalkoxy, phenyl orphenoxy, each phenyl or phenoxy group optionally substituted with one ormore groups independently selected from halogen, C₁–C₄ alkyl, C₁–C₄alkoxy, C₁–C₄ haloalkyl and C₁–C₄ haloalkoxy.

The acetyl groups in Formulae VIa, VIb or VIc can be readily removed bystandard chemical manipulations to provide compounds of Formula I. Forexample, removal of acetyl groups can be effected by treatment withhydrochloric acid in ethanol. With aromatic amines, e.g., Formulae VIband VIc, this deacylation procedure will result in the formation of thehydrochloride salt of Formula Ia, which can be isolated or furtherprocessed with base to provide compounds of Formula Ia as the freebases. The conversion of compounds of Formulae VIa, VIb or VIc tocompounds of Formula Ia may be accomplished either by isolating thecompounds of Formulae VIa, VIb and VIc and removing the acetyl groups ina separate step or by treating the crude reaction products from thehydrogenation step directly.

In the method of Schemes 1 and 1a, n is typically 0, but as one skilledin the art will realize, numerous chemical modifications of thethioether moiety are possible and may be employed when necessary tofacilitate this transformation. These include modifications wherein thethioether moiety is oxidized to the sulfoxide (n is 1) or sulfone (n is2). Compounds of Formula II wherein n is 1 or 2 can be prepared bytreating the corresponding compounds of Formula II wherein n is 0 withoxidizing agents, such as but not limited to, 3-chloroperoxybenzoicacid, in inert solvents, such as dichloromethane. A number of well-knownprocedures are available for the oxidation of sulfur; for example, seeJ. March, Advanced Organic Chemistry; 3rd edition, John Wiley: New York,(1985), p 1089. As this entails an additional reaction step, for themethod of Schemes 1 and 1a, n is preferably 0.

As outlined in Scheme 2, compounds of Formula II wherein n is 0 can beprepared from the corresponding aromatic alcohols or amines of Formula Iby treatment with the appropriate thioether of Formula VII and achlorinating agent, such as tert-butyl hypochlorite orN-chlorosuccinimide, followed by treatment with a base, such astriethylamine or sodium methoxide in methanol, to effect rearrangementaccording to the methods described in P. G. Gassman, G. Gruetzmacher, J.Am. Chem. Soc. 1973, 95, 588–589, P. G. Gassman, G. Gruetzmacher, Org.Syn., Coll. Vol. VI, 581–583; P. G. Gassman, H. R. Drewes, J. Am. Chem.Soc. 1978, 100, 7600–7610; and P. G. Gassman, D. R. Amick, J. Am. Chem.Soc. 1978, 100, 7611–7619.

wherein

-   -   n is 0;    -   A is O or NH;    -   L is H;    -   K is, together with the two contiguous linking carbon atoms, a        phenyl ring, a 5- or 6-membered heteroaromatic ring or an        aromatic 8-, 9- or 10-membered fused carbobicyclic or        heterobicyclic ring system wherein each ring or ring system is        optionally substituted;    -   R¹ is H, C₁ to C₄ alkyl or CO₂R³;    -   R² is H or C₁ to C₄ alkyl;    -   R³ is C₁ to C₄ alkyl; and    -   R⁴ is CHR¹R².        When A is NH, an intermediate ylid can be isolated after        contacting the Formula III compound and thioether of Formula II        with the chlorinating agent in a water-immiscible solvent and        then washing with aqueous base such as sodium hydroxide        solution; this ylid can then be rearranged to the compound of        Formula II wherein n is 0 and L is H in the absence of solvent,        in a protic solvent such as methanol or water, in an aprotic        solvent in the presence of a suitable base, or in a combination        of a protic solvent, an aprotic solvent and a base as described        below for the conversion of Formula V to Formula II in Scheme 3.

Compounds of Formula II wherein n is 0, L is H and A is NH can also beprepared from the corresponding compounds of Formula III as shown inScheme 3.

wherein

-   -   n is 0;    -   A is NH;    -   L is H;    -   K is, together with the two contiguous linking carbon atoms, a        phenyl ring, a 5- or 6-membered heteroaromatic ring or an        aromatic 8-, 9- or 10-membered fused carbobicyclic or        heterobicyclic ring system wherein each ring or ring system is        optionally substituted;    -   R¹ is H, C₁ to C₄ alkyl or CO₂R³;    -   R² is H or C₁ to C₄ alkyl;    -   R³ is C₁ to C₄ alkyl; and    -   R⁴ is CHR¹R².        In the method of Scheme 3, intermediate sulfilimine        (alternatively named iminosulfurane) ylid compounds of Formula V        are prepared from aromatic amines of Formula III (A is NH) by        reaction with a dialkyl sulfoxide of Formula IV which has been        “activated” by treatment with an agent such as acetic anhydride,        trifluoroacetic anhydride, trifluoromethanesulfonic anhydride,        cyclohexylcarbodiimide, sulfur trioxide, or phosphorus pentoxide        according to the procedures of P. Claus and W. Vycudilik        Tetrahedron Lett. 1968, 3607–3610; Monatsch. Chem. 1970, 101,        396–404; and T. E. Varkey, G. F. Whitfield and D. Swern J. Org.        Chem. 1974, 39, 3365–3372. The reaction is conducted in a        suitable organic solvent such as dichloromethane or dimethyl        sulfoxide. The reaction is conducted at a temperature between        −70 and 25° C.; the optimal temperature depends on the solvent        and reagent used.

In the method of Scheme 3, the intermediate ylid compounds of Formula Vcan be isolated or used without isolation in the subsequentrearrangement step. The rearrangement can be achieved in the absence ofsolvent (see U.S. Pat. No. 4,496,765), in a protic solvent such asmethanol or water (see P. Claus and W. Rieder, Monatsh. Chem. 1972, 103,1163–1177), in an aprotic solvent in the presence of a suitable base, orin a combination of a protic solvent, an aprotic solvent and a base. Avariety of aprotic solvents can be used in this reaction, includingchlorinated alkanes such as dichloromethane, ethers such astetrahydrofuran, amides such as N,N-dimethyl-formamide, aromaticsolvents such as benzene, chlorobenzene, toluene, xylene, etc. A varietyof bases can be used, including tertiary alkyl and benzylamines liketriethylamine, N,N-dimethylbenzylamine and1,8-diazabicyclo[5.4.0]undec-7-ene, and alkali metal alkoxides such assodium methoxide, sodium ethoxide and potassium tert-butoxide, which canbe solubilized using crown ethers and the like. Alkali metal alkoxidesare especially useful for effecting the rearrangement to Formula II insolvents comprising an aprotic solvent, and in particular, it has beendiscovered that a methanolic solution of sodium methoxide added totoluene as the bulk solvent works well for effecting the rearrangement.The temperature at which the reaction is conducted in solvents isusually in the range of about 40–110° C., but in the absence of solvent,the temperature needed is generally higher, i.e. about 100–200° C. Whenthe reaction is conducted in the absence of solvent, inclusion of acatalytic amount of an organic base or weak acid such as succinimide asdescribed by U.S. Pat. No. 4,496,765 can increase the rate ofrearrangement. As one skilled in the art will realize, operablevariations embraced by the method of Scheme 3 include generating a salt(e.g., a hydrochloride, sulfate or bisulfate) of the Formula V ylid, andthen treating the salt with the appropriate amount of base to generatethe free ylid of Formula V. This may be done as a separate step or anintegral part of the step involving rearrangement to the compounds ofFormula II.

Besides offering low cost and facilitating waste treatment, sulfurtrioxide as activating agent in the method of Scheme 3 has beendiscovered to be effective in providing high yields of compounds ofFormula II, which can then be reduced using the method of Scheme 1 togive compounds of Formula I. Accordingly this represents a preferredaspect of the present invention. Furthermore, the reaction using thesulfur trioxide complex of a sulfoxide compound of Formula IV has beendiscovered to be conveniently carried out with excellent yields usingmuch smaller amounts of the Formula IV sulfoxide than directed by T. E.Varkey, G. F. Whitfield and D. Swern, J. Org. Chem. 1974, 39, 3365–3372by conducting the reaction in an inert solvent. The solvent must beinert to the high electrophilicity of the complex of sulfur trioxidewith the sulfoxide IV. Generally the solvent is chosen from fluorinatedand chlorinated alkane and cycloalkane solvents. Specifically useful aresolvents comprising at least one of dichloromethane and1,1,2,2-tetrachloroethane. Most preferred for this reaction is a solventcomprising dichloromethane, which has been discovered to give excellentyields, as well as being relatively inexpensive and easily removed fromthe reaction product by evaporation. The reaction can generally beconducted in the range between the freezing and boiling point of thesolvent, but is typically conducted between about −10 and 40° C.

Typically, nearly 2 moles of sulfur trioxide per mole of aromatic amine(Formula III, A is NH) has been found needed to obtain completeconversion, so the most useful amounts of sulfur trioxide are generallyabout 1.8 to 2.2 and more preferably about 1.9 to 2.1 equivalentsrelative to amount of the aromatic amine of Formula III. (As used hereinone skilled in the art recognizes the term “equivalents” is effectivelysynonymous with the term “moles” for sulfur trioxide and the sulfoxideIV, and also for the aromatic amine III (A is NH) if it has a singleamino functionality.) At least one mole of the sulfoxide IV per mole ofaromatic amine is needed for complete conversion. Furthermore at leastone mole of sulfoxide IV is typically used per mole of sulfur trioxideso that all of the sulfur trioxide is complexed. The solvent conditionsof the present invention obviate need for considerable excesses of thesulfoxide IV, which would add to cost and waste treatment concerns.Therefore the amount of sulfoxide of Formula IV is generally in therange of about 0.5 to 3, more preferably in the range of about 1 to 2,and most preferably in the range of about 1 to 1.5 equivalents relativeto the amount of sulfur trioxide. The amount of sulfoxide of Formula IVis generally in the range of about 1 to 6, more preferably in the rangeof about 1.8 to 4, and most preferably in the range of about 1.8 to 3equivalents relative to the amount of aromatic amine of Formula III.

The reaction generally requires from 0.1 to 10 hours, and can bemonitored by conventional techniques such as chromatography and nuclearmagnetic resonance spectroscopy. After the reaction is complete, thereaction mixture is washed with an aqueous solution of base. Thereaction between aromatic amine, sulfoxide and sulfur trioxide isbelieved to afford the product of Formula V in its protonated form. Thebase then liberates the free ylid species of Formula V as well asneutralizes other acidic byproducts in the reaction mixture.Accordingly, the amount of base is preferably at least 2 equivalents pereach mole of sulfur trioxide used in the reaction, although typically anexcess of base is used for convenience. Suitable bases include alkalimetal carbonates, hydroxides and phosphates. For example, sodiumhydroxide works well for this purpose. The ylid of Formula V can then beisolated by conventional techniques, such as evaporation of the solvent,crystallization, etc.

It is recognized that some reagents and reaction conditions describedabove for preparing compounds of Formula I may not be compatible withcertain functionalities present in the intermediates. In theseinstances, the incorporation of protection/deprotection sequences orfunctional group interconversions into the synthesis will aid inobtaining the desired products. The use and choice of the protectinggroups will be apparent to one skilled in chemical synthesis (see, forexample, T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art willrecognize that, in some cases, after the introduction of a given reagentas it is depicted in any individual scheme, it may be necessary toperform additional routine synthetic steps not described in detail tocomplete the synthesis of compounds of Formula I. One skilled in the artwill also recognize that it may be necessary to perform a combination ofthe steps illustrated in the above schemes in an order other than thatimplied by the particular sequence presented to prepare the compounds ofFormula I.

One skilled in the art will also recognize that compounds of Formula Iand the intermediates described herein can be subjected to variouselectrophilic, nucleophilic, radical, organometallic, oxidation, andreduction reactions to add substituents or modify existing substituents.

Without further elaboration, it is believed that one skilled in the artusing the preceding description can utilize the present invention to itsfullest extent. The following Examples are, therefore, to be construedas merely illustrative, and not limiting of the disclosure in any waywhatsoever. Percentages are by weight except for chromatographic solventmixtures or where otherwise indicated. Parts and percentages forchromatographic solvent mixtures are by volume unless otherwiseindicated. ¹H NMR spectra are reported in ppm downfield fromtetramethylsilane; “s” means singlet, “d” means doublet, “t” meanstriplet, “q” means quartet, “m” means multiplet, “dd” means doublet ofdoublets, “dt” means doublet of triplets, “br s” means broad singlet.

EXAMPLE 1 Preparation of 2′-methyl-6′-phenoxyacetanilide

Step 1: Preparation of 2′-[(methylthio)methyl]-6′-phenoxyacetanilide

In a 3-necked, round bottom flask equipped with a mechanical stirrer2-phenoxyaniline (37.0 g, 0.2 mol) was dissolved in dichloromethane (350mL). A vigreux column was attached and part of the dichloromethane (100mL) was distilled off. The reaction solution was then cooled to −5° C.using a dry ice/acetone bath. Dimethyl sulfide (18 mL, 0.25 mol) wasadded while the temperature of the reaction solution was maintainedbetween −5 and 0° C. Then N-chlorosuccinimide (27.0 g, 0.2 mol) wasadded over a 10 minute period while the temperature of the reactionmixture was maintained between −5 and 0° C. After addition was complete,an ice/water bath was substituted for the dry ice/acetone bath tomaintain the temperature near 0° C. while the reaction mixture wasstirred for 30 minutes. Then triethylamine (60 mL, 0.42 mol) was added,and the mixture was heated at reflux for 2 hours. After the reactionmixture cooled to room temperature, a solution of sodium sulfite (20 g)in water (500 mL) was added to the stirred reaction mixture. After 10minutes, the reaction mixture was decanted, and the organic layer waswashed with water (500 mL). A 250 mL, 3-necked round bottom flask wasfitted with a distillation head and an addition funnel. Part of theorganic layer (100 mL) was poured into the flask, and the remainder ofthe organic layer was poured into the addition funnel. The organic layermaterial was added to the flask in 50 mL portions while solvent wasremoved by distillation. After all of the organic layer had been addedand the flask temperature reached 110° C., the residual material wascooled to room temperature and diluted with cyclohexane (50 mL). Themixture was then heated to 60° C., and acetic anhydride (20 mL) wasadded over a 15 minute period. After the reaction mixture was held at60° C. for one hour, it was cooled to room temperature and seeded withproduct crystals. After the mixture was stirred for one hour, theproduct was collected by filtration. The collected material wasrepeatedly washed with hexanes and petroleum ether and dried in vacuo toprovide a crystalline product (24.41 g, 59% yield, 98% purity by gaschromatography area). This product was purified by recrystallizationfrom toluene to afford product (13.24 g) that showed no impurity peaksby gas chromatography and ¹H NMR.

Step 2: Preparation of 2′-methyl-6′-phenoxyacetanilide

Pressure tubes (C276 Hastalloy metal, 10 mL) were charged with2′-[(methylthio)-methyl]-6′-phenoxyacetanilide (i.e. product of Step 1,weight listed in Table A for sulfide), catalyst (identity and weightlisted in Table A) and solvent (identity and weight listed in Table A).With shaking, the contents of the pressure tubes were hydrogenated atthe pressures, temperatures and periods of time listed in Table A. Thecatalysts were then removed by filtration, and the filtrates wereanalyzed by gas chromatography to determine percent conversion based onpeak area.

TABLE A Preparation of 2′-methyl-6′-phenoxyacetanilide bypalladium-catalyzed hydrogenation of2′-[(methylthio)methyl]-6′-phenoxyacetanilide Catalyst Sulfide SolventTemp. Pressure Time % Run Catalyst* wt. (g) wt. (g) Solvent wt. (g) (°C.) (kPa) (h) Conversion 1 Pd 0.441 0.591 EtOAc 5.278 175 2760 4 98 2 Pd0.385 0.518 MeOH 4.365 60 3450 4 10 3 Pd 0.445 0.600 EtOAc 5.288 1751720 4 70 4 Pd 0.0438 0.594 EtOAc 5.288 175 2760 4 20 5 Pd 0.00934 0.583EtOAc 5.273 175 2760 4  9 6 Pd 0.444 0.508 EtOAc 5.283 70 3450 4 <5 7 Pd0.443 0.500 EtOAc 5.279 70 3450 4 <5 8 Pd 0.444 0.605 Toluene 5.270 1752760 4 66 9 Pd 0.441 0.600 EtOAc 5.281 175 2760 4 95** 10 Pd-Sn 0.0450.594 EtOAc 5.278 175 2760 7 40 11 None — 0.599 EtOAc 5.276 175 2760 412*** *Palladium (Pd) catalyst used was 5% palladium on carbon fromEngelhard (864A-3-288-1). Palladium-tin (Pd-Sn) catalyst used was 5%palladium and 1% tin on carbon from Engelhard (864A-3-290-1). **Unknownpeak also seen by gas chromatography. ***Run 11 may suggest that theHastalloy metal of the hydrogenation vessel has some catalyticproperties.

EXAMPLE 2 Preparation of 2-methyl4-(trifluoromethyl)aniline as itsHydrochloride Salt

The gas chromatography (GC) analyses, for Example 2 used aHewlett-Packard 5890 Series II Plus Gas Chromatograph with a 5 m long,530 μm diameter HP-1 (dimethylpolysiloxane, available from AgilentTechnologies) column and a thermal program of 90° C. for 1 min, then 20°C./min. increase to a final temperature of 250° C., which was held for 5min. Helium was used as the carrier gas at a flow rate of 10 mL/min.

Step 1: Preparation ofS,S-dimethyl-N-[4-(trifluoromethyl)phenyl]sulfilimine

Sulfur trioxide (4.84 g, 60.5 mmol) in dichloromethane (10 mL) was addedto dimethyl sulfoxide (4.84 g, 62.0 mmol) in dichloromethane (10 mL) at−5 to 0° C. When the addition was complete 4-(trifluoromethyl)aniline(5.00 g, 31.0 mmol) was added dropwise. The mixture was allowed to warmto ambient temperature. After about 1 h the mixture was diluted withdichloromethane (80 mL) and washed with sodium hydroxide (1 N, 100 mL),dried and evaporated to give the title product as a solid (6.58 g, 96%yield).

¹H NMR (CDCl₃) δ 7.35 (d, 2H), 6.84 (d, 2H), 2.66 (s, 6H).

Step 2: Preparation of2-[(methylthio)methyl]-4-(trifluoromethyl)benzenamine

Sodium methoxide in methanol (1.95 g, 25%, 9.02 mmol) was added to theproduct from Step 1 (2 g, 9.04 mmol) in toluene (15 mL). The mixture waswarmed to about 80° C. After 1 h the mixture was allowed to cool and waspoured into water (100 mL). The mixture was extracted with ethyl acetate(2×100 mL) and the combined extracts were dried and evaporated to givethe title product as a solid (1.8 g, 90% yield), melting at 65.5–67.5°C. after recrystallization from hexanes.

IR (nujol) ν 3419, 3333, 1629, 1584, 1512, 1440, 1334, 1302, 1235, 1194,1139, 1078, 979, 904, 832 cm⁻¹. ¹H NMR (CDCl₃) δ 7.35 (dd, J=8.2, 1.5Hz, 1H), 7.26 (s, 1H), 6.72 (d, J=8.4 Hz, 1H), 4.39 (br s, 2H), 3.69 (s,2H), 1.99 (3H, s). MS 221 (M⁺).

Step 3: Preparation of N-[2-methyl-4-(trifluoromethyl)phenyl]acetamide

A glass-lined shaker tube was charged with the product from Step 2 (5.00g, 22.6 mmol), catalyst (Engelhard 864A-3-290-1, 5% Pd, 1% Sn/C, 0.630g), and acetic anhydride (80 mL). The tube was pressurized to 100 psi(690 kPa) with hydrogen at ambient temperature, then heated to 150° C.and shaken for 6 hours. The pressure was maintained at 140 psi (965 kPa)during this time by periodically repressurizing with hydrogen. After 6hours, the reaction vessel was cooled to ambient temperature and theremaining hydrogen vented to release the pressure. GC analysis showed amixture of the two products,N-[2-methyl-4-(trifluoromethyl)phenyl]acetamide andN-acetyl-N-[2-methyl-4-(trifluoromethyl)phenyl]acetamide, and the twoacylated starting materials,N-[2-[(methylthio)methyl]-4-(trifluoromethyl)phenyl]acetamide andN-acetyl-N-[2-[(methylthio)methyl]-4-(trifluoromethyl)phenyl]acetamide,in a 6:55:6:33 peak area ratio, respectively.

The reaction mixture was filtered through Celite® diatomaceous filteraid, washed with ethyl acetate, and the filtrate concentrated in vacuoto an orange oil. To convert the N,N-diacetyl derivatives to theirrespective N-acetyl analogues, 4-(dimethyl-amino)pyridine (DMAP) (0.500g) was added to a solution of the oil in ethanol (50 mL), and thissolution was heated at reflux for 4 hours. GC analysis showed a53:8:38:1 peak area ratio. After evaporation, the residue was purifiedby flash column chromatography (60:40 hexanes-ethyl acetate).N-[2-methyl-4-(trifluoromethyl)phenyl]acetamide was obtained as a whitesolid (2.85 g, 58% yield). The starting material was recovered as itsacetylated derivativeN-[2-[(methylthio)methyl]-4-(trifluoromethyl)phenyl]acetamide in 31%yield (1.84 g).

N-[2-methyl-4-(trifluoromethyl)phenyl]acetamide:

¹H NMR (CDCl₃) δ 8.074 (br d, 7.3 Hz, 1H), 7.4–7.5 (m, 2 H), 7.080 (brs, 1H), 2.313 (s, 3H), 2.235 (s, 3H). LC/MS AP⁺: 218 (M⁺+1) and 259(M⁺+1+41; acetonitrile adduct). m.p. 159.5–160.5° C. R_(f) was 0.21(60:40 hexanes-ethyl acetate), GC retention time: 3.52 min.

N-acetyl-N-[2-methyl4-(trifluoromethyl)phenyl]acetamide:

¹H NMR (CDCl₃) δ 7.599 (s, 1H), 7.570 (d, J=8.0 Hz, 1H), 7.214 (d, J=8.0Hz, 1H), 2.278 (s, 6H), 2.230 (s, 3H). LC/MS AP⁺: 259 (M⁺−42+41;corresponding to acetonitrile adduct after loss of one acetyl group).m.p. 70–72° C. R_(f) was 0.70 (60:40 hexanes-ethyl acetate). GCretention time: 3.432 min, peak was 97.8% of total area of all peaksrecorded.

Step 4: Preparation of 2-methyl-4-(trifluoromethyl)aniline Hydrochloride

A solution of N-[2-methyl-4-(trifluoromethyl)phenyl]acetamide (5.17 g)and aqueous hydrochloric acid (37%, 12 mL) in ethanol (24 mL) was heatedto reflux for 3 hours and then stirred at ambient temperature for 48hours. GC analysis of the reaction mixture showed a 98:2 peak area ratioof 2-methyl-4-(trifluoromethyl)aniline to starting material.2-Methyl-4-(trifluoromethyl)aniline hydrochloride was obtained as awhite solid by filtering the reaction mixture and washing the solidswith ethyl acetate. A second crop of 2-methyl-4-(trifluoromethyl)anilinehydrochloride was obtained by evaporating the filtrate to dryness,triturating the residue in ethyl acetate, then filtering, providing atotal of 4.27 g (85% yield).

¹H NMR (CD₃OD) δ 7.726 (s, 1H), 7.664 (d, J=8.5 Hz, 1H), 7.544 (d, J=8.4Hz, 1H), 2.484 (s, 3H). LC/MS AP⁺: 176 (M⁺), 217 (M⁺+41, acetonitrileadduct). GC retention times: 1.74 min. for2-methyl-4-(trifluoromethyl)aniline, 3.53 min. forN-[2-methyl-4-(trifluoromethyl)phenyl]acetamide.

By the methods described herein, including specifically the proceduresillustrated by Example 1, together with methods known in the art, thefollowing compounds of Tables 1A–3D can be prepared. The followingabbreviations are used in the Tables which follow: t means tertiary, smeans secondary, n means normal, i means iso, Me means methyl, Et meansethyl, Pr means propyl, i-Pr means isopropyl, Bu means butyl and Phmeans phenyl. “Ex.” refers to the above Examples.

TABLE 1A

L is H. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH Me H — O Me Me — NHMe Me — O Et H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NH CO₂Me n-Bu— NH H H 4-F NH H H 4-F O H H 4-Cl NH H H 4-Cl O H H 4-Br NH H H 4-Br OH H 4-I NH H H 4-I O H H 4-CF₃ NH (Ex. 2, Step 4) H H 4-CF₃ O H H 4-PhNH H H 4-OPh NH H H 6-OPh NH H H 4-O(Ph-2′-Me) NH H H 4-OCH₃ NH H H4-OCH₃ O H H 4-OCF₂H NH H H 4-OCF₂H O H H 4-Me NH H H 4-Me O H H4-OCH₂CF₃ NH Me H 4-CF₃ NH H H 3,5-di-Me NH Me Me 4-CF₃ NH Me Me 4-CF₃ OEt H 4-CF₃ NH n-Bu n-Bu 4-CF₃ NH CO₂Me H 4-CF₃ NH CO₂Me Me 4-CF₃ NHCO₂Me n-Bu 4-CF₃ NH H H 3,4,5-tri-Me NH H H 3,4,5-tri-OMe NH H H 6-CF₃NH H H 6-F NH i-Pr H 4-CF₃ NH H H 6-Ph NH H H 6-Ph O H H 4-O(Ph-4′-Cl)NH H H 4-(Ph-4′-Cl) NH L is C(O)CH₃. R¹ R² (R⁵)_(m) A H H — NH H H — OMe H — NH Me H — O Me Me — NH Me Me — O Et H — NH n-Bu n-Bu — NH CO₂Me H— NH CO₂Me Me — NH CO₂Me n-Bu — NH H H 4-F NH H H 4-F O H H 4-Cl NH H H4-Cl O H H 4-Br NH H H 4-Br O H H 4-I NH H H 4-I O H H 4-CF₃ NH (Ex. 2,Step 3) H H 4-CF₃ O H H 4-Ph NH H H 4-OPh NH H H 6-OPh NH (Ex. 1, Step2) H H 4-O(Ph-2′-Me) NH H H 4-OCH₃ NH H H 4-OCH₃ O H H 4-OCF₂H NH H H4-OCF₂H O H H 4-Me NH H H 4-Me O H H 4-OCH₂CF₃ NH Me H 4-CF₃ NH H H3,5-di-Me NH Me Me 4-CF₃ NH Me Me 4-CF₃ O Et H 4-CF₃ NH n-Bu n-Bu 4-CF₃NH CO₂Me H 4-CF₃ NH CO₂Me Me 4-CF₃ NH CO₂Me n-Bu 4-CF₃ NH H H3,4,5-tri-Me NH H H 3,4,5-tri-OMe NH H H 6-CF₃ NH H H 6-F NH i-Pr H4-CF₃ NH H H 6-Ph NH H H 6-Ph O H H 4-O(Ph-4′-Cl) NH H H 4-(Ph-4′-Cl) NHR¹ R² (R⁵)_(m) A L H H — NH C(O)CH₂CH₃ H H — O C(O)CH₂CH₃ H H — NHC(O)CF₃ H H — NH C(O)OCH₃ H H — O C(O)OC(CH₃)₃ H H — NH C(O)OC(CH₃)₃ H H— NH C(O)OCH₂CH₂Cl H H — NH C(O)O(CH₂)₃CH₃ H H — NH C(O)(CH₂)₃CH₃ H H —NH C(O)H Me H — NH C(O)CF₃ Me H — NH C(O)OCH₃ Me Me — NH C(O)OC(CH₃)₃ HH 4-F NH C(O)O(CH₂)₂CH₃ H H 4-Cl O C(O)CH₂CH₃ H H 4-CF₃ NH C(O)OC(CH₃)₃H H 4-Me NH C(O)OCH₂CH₂Br H H 6-CF₃ NH C(O)CF₃ H H 6-F NH C(O)OCH₃ H H4-Ph NH C(O)OC(CH₃)₃ H H 4-OPh NH C(O)(CH₂)₃CH₃ H H 6-OPh NH C(O)CF₃ H H6-Ph NH C(O)OCH₂CH₃ H H 4-OCH₃ NH C(O)CH₂CH₃ H H 3,4,5-tri-Me OC(O)C(CH₃)₃ H H 3,4,5-tri-OMe NH C(O)CF₃

TABLE 1B

L is H. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH Me H — O Me Me — NHEt H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NH H H 4-F NH H H 4-F OH H 4-Cl NH H H 4-Br NH H H 4-CF₃ NH H H 4-OCH₃ NH H H 4-OCF₂H NH H H4-Me NH H H 8-CH₃ NH Me H 4-CF₃ NH H H 3,5-di-Me NH Me Me 4-CF₃ NH Me Me4-CF₃ O Et H 4-CF₃ NH n-Bu n-Bu 4-CF₃ NH CO₂Me H 4-CF₃ NH H H 6-CF₃ NH HH 6-F NH i-Pr H 4-CF₃ NH L is C(O)CH₃. R¹ R² (R⁵)_(m) A H H — NH H H — OMe H — NH Me H — O Me Me — NH Et H — NH n-Bu n-Bu — NH CO₂Me H — NHCO₂Me Me — NH H H 4-F NH H H 4-F O H H 4-Cl NH H H 4-Br NH H H 4-CF₃ NHH H 4-OCH₃ NH H H 4-OCF₂H NH H H 4-Me NH H H 8-CH₃ NH Me H 4-CF₃ NH H H3,5-di-Me NH Me Me 4-CF₃ NH Me Me 4-CF₃ O Et H 4-CF₃ NH n-Bu n-Bu 4-CF₃NH CO₂Me H 4-CF₃ NH H H 6-CF₃ NH H H 6-F NH i-Pr H 4-CF₃ NH

TABLE 1C

L is H. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH Me H — O Me Me — NHEt H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NH H H 4-F NH H H 4-F OH H 4-Cl NH H H 4-Br NH H H 4-CF₃ NH H H 4-OCH₃ NH H H 4-OCF₂H NH H H4-Me NH H H 4-OCH₂CF₃ NH Me H 4-CF₃ NH H H 3,5-di-Me NH Me Me 4-CF₃ NHMe Me 4-CF₃ O Et H 4-CF₃ NH n-Bu n-Bu 4-CF₃ NH CO₂Me H 4-CF₃ NH i-Pr H4-CF₃ NH L is C(O)CH₃. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH Me H— O Me Me — NH Et H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NH H H4-F NH H H 4-F O H H 4-Cl NH H H 4-Br NH H H 4-CF₃ NH H H 4-OCH₃ NH H H4-OCF₂H NH H H 4-Me NH H H 4-OCH₂CF₃ NH Me H 4-CF₃ NH H H 3,5-di-Me NHMe Me 4-CF₃ NH Me Me 4-CF₃ O Et H 4-CF₃ NH n-Bu n-Bu 4-CF₃ NH CO₂Me H4-CF₃ NH i-Pr H 4-CF₃ NH

TABLE 1D

L is H. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH Me H — O Me Me — NHEt H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NH H H 6-F NH H H 6-F OH H 6-Cl NH H H 6-Br NH H H 6-CF₃ NH H H 6-OCH₃ NH H H 6-OCF₂H NH H H6-Me NH H H 6-OCH₂CF₃ NH Me H 6-CF₃ NH H H 3,5-di-Me NH Me Me 6-CF₃ NHMe Me 6-CF₃ O Et H 6-CF₃ NH n-Bu n-Bu 6-CF₃ NH CO₂Me H 6-CF₃ NH i-Pr H6-CF₃ NH L is C(O)CH₃. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH Me H— O Me Me — NH Et H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NH H H6-F NH H H 6-F O H H 6-Cl NH H H 6-Br NH H H 6-CF₃ NH H H 6-OCH₃ NH H H6-OCF₂H NH H H 6-Me NH H H 6-OCH₂CF₃ NH Me H 6-CF₃ NH H H 3,5-di-Me NHMe Me 6-CF₃ NH Me Me 6-CF₃ O Et H 6-CF₃ NH n-Bu n-Bu 6-CF₃ NH CO₂Me H6-CF₃ NH i-Pr H 6-CF₃ NH

TABLE 2A

L is H, and n is 0. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH Me H — OMe Me — NH Me Me — O Et H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NHCO₂Me n-Bu — NH H H 4-F NH H H 4-F O H H 4-Cl NH H H 4-Cl O H H 4-Br NHH H 4-Br O H H 4-I NH H H 4-I O H H 4-CF₃ NH (Ex. 2, Step 2) H H 4-CF₃ OH H 4-Ph NH H H 4-OPh NH H H 6-OPh NH H H 4-O(Ph-2′-Me) NH H H 4-OCH₃ NHH H 4-OCH₃ O H H 4-OCF₂H NH H H 4-OCF₂H O H H 4-Me NH H H 4-Me O H H4-OCH₂CF₃ NH Me H 4-CF₃ NH H H 3,5-di-Me NH Me Me 4-CF₃ NH Me Me 4-CF₃ OEt H 4-CF₃ NH n-Bu n-Bu 4-CF₃ NH CO₂Me H 4-CF₃ NH CO₂Me Me 4-CF₃ NHCO₂Me n-Bu 4-CF₃ NH H H 3,4,5-tri-Me NH H H 3,4,5-tri-OMe NH H H 6-CF₃NH H H 6-F NH i-Pr H 4-CF₃ NH H H 6-Ph NH H H 6-Ph O H H 4-O(Ph-4′-Cl)NH H H 4-(Ph-4′-Cl) NH L is C(O)CH₃, and n is 0. R¹ R² (R⁵)_(m) A H H —NH H H — O Me H — NH Me H — O Me Me — NH Me Me — O Et H — NH n-Bu n-Bu —NH CO₂Me H — NH CO₂Me Me — NH CO₂Me n-Bu — NH H H 4-F NH H H 4-F O H H4-Cl NH H H 4-Cl O H H 4-Br NH H H 4-Br O H H 4-I NH H H 4-I O H H 4-CF₃NH (Ex. 2, Step 2) H H 4-CF₃ O H H 4-Ph NH H H 4-OPh NH H H 6-OPh NH(Ex. 1, Step 1) H H 4-O(Ph-2′-Me) NH H H 4-OCH₃ NH H H 4-OCH₃ O H H4-OCF₂H NH H H 4-OCF₂H O H H 4-Me NH H H 4-Me O H H 4-OCH₂CF₃ NH Me H4-CF₃ NH H H 3,5-di-Me NH Me Me 4-CF₃ NH Me Me 4-CF₃ O Et H 4-CF₃ NHn-Bu n-Bu 4-CF₃ NH CO₂Me H 4-CF₃ NH CO₂Me Me 4-CF₃ NH CO₂Me n-Bu 4-CF₃NH H H 3,4,5-tri-Me NH H H 3,4,5-tri-OMe NH H H 6-CF₃ NH H H 6-F NH i-PrH 4-CF₃ NH H H 6-Ph NH H H 6-Ph O H H 4-O(Ph-4′-Cl) NH H H 4-(Ph-4′-Cl)NH n is 0. R¹ R² (R⁵)_(m) A L H H — NH C(O)CH₂CH₃ H H — O C(O)CH₂CH₃ H H— NH C(O)CF₃ H H — NH C(O)OCH₃ H H — O C(O)OC(CH₃)₃ H H — NHC(O)OC(CH₃)₃ H H — NH C(O)OCH₂CH₂Cl H H — NH C(O)O(CH₂)₃CH₃ H H — NHC(O)(CH₂)₃CH₃ H H — NH C(O)H Me H — NH C(O)CF₃ Me H — NH C(O)OCH₃ Me Me— NH C(O)OC(CH₃)₃ H H 4-F NH C(O)O(CH₂)₂CH₃ H H 4-Cl O C(O)CH₂CH₃ H H4-CF₃ NH C(O)OC(CH₃)₃ H H 4-Me NH C(O)OCH₂CH₂Br H H 6-CF₃ NH C(O)CF₃ H H6-F NH C(O)OCH₃ H H 4-Ph NH C(O)OC(CH₃)₃ H H 4-OPh NH C(O)(CH₂)₃CH₃ H H6-OPh NH C(O)CF₃ H H 6-Ph NH C(O)OCH₂CH₃ H H 4-OCH₃ NH C(O)CH₂CH₃ H H3,4,5-tri-Me O C(O)C(CH₃)₃ H H 3,4,5-tri-OMe NH C(O)CF₃ L is H, and nis 1. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH Me H — O Me Me — NH MeMe — O Et H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NH CO₂Me n-Bu —NH H H 4-F NH H H 4-F O H H 4-Cl NH H H 4-Cl O H H 4-Br NH H H 4-Br O HH 4-I NH H H 4-I O H H 4-CF₃ NH H H 4-CF₃ O H H 4-Ph NH H H 4-OPh NH H H6-OPh NH H H 4-O(Ph-2′-Me) NH H H 4-OCH₃ NH H H 4-OCH₃ O H H 4-OCF₂H NHH H 4-OCF₂H O H H 4-Me NH H H 4-Me O H H 4-OCH₂CF₃ NH Me H 4-CF₃ NH H H3,5-di-Me NH Me Me 4-CF₃ NH Me Me 4-CF₃ O Et H 4-CF₃ NH n-Bu n-Bu 4-CF₃NH CO₂Me H 4-CF₃ NH CO₂Me Me 4-CF₃ NH CO₂Me n-Bu 4-CF₃ NH H H3,4,5-tri-Me NH H H 3,4,5-tri-OMe NH H H 6-CF₃ NH H H 6-F NH i-Pr H4-CF₃ NH H H 6-Ph NH H H 6-Ph O H H 4-O(Ph-4′-Cl) NH H H 4-(Ph-4′-Cl) NHL is C(O)CH₃, and n is 1. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH MeH — O Me Me — NH Me Me — O Et H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂MeMe — NH CO₂Me n-Bu — NH H H 4-F NH H H 4-F O H H 4-Cl NH H H 4-Cl O H H4-Br NH H H 4-Br O H H 4-I NH H H 4-I O H H 4-CF₃ NH H H 4-CF₃ O H H4-Ph NH H H 4-OPh NH H H 6-OPh NH H H 4-O(Ph-2′-Me) NH H H 4-OCH₃ NH H H4-OCH₃ O H H 4-OCF₂H NH H H 4-OCF₂H O H H 4-Me NH H H 4-Me O H H4-OCH₂CF₃ NH Me H 4-CF₃ NH H H 3,5-di-Me NH Me Me 4-CF₃ NH Me Me 4-CF₃ OEt H 4-CF₃ NH n-Bu n-Bu 4-CF₃ NH CO₂Me H 4-CF₃ NH CO₂Me Me 4-CF₃ NHCO₂Me n-Bu 4-CF₃ NH H H 3,4,5-tri-Me NH H H 3,4,5-tri-OMe NH H H 6-CF₃NH H H 6-F NH i-Pr H 4-CF₃ NH H H 6-Ph NH H H 6-Ph O H H 4-O(Ph-4′-Cl)NH H H 4-(Ph-4′-Cl) NH L is H, and n is 2. R¹ R² (R⁵)_(m) A H H — NH H H— O Me H — NH Me H — O Me Me — NH Me Me — O Et H — NH n-Bu n-Bu — NHCO₂Me H — NH CO₂Me Me — NH CO₂Me n-Bu — NH H H 4-F NH H H 4-F O H H 4-ClNH H H 4-Cl O H H 4-Br NH H H 4-Br O H H 4-I NH H H 4-I O H H 4-CF₃ NH HH 4-CF₃ O H H 4-Ph NH H H 4-OPh NH H H 6-OPh NH H H 4-O(Ph-2′-Me) NH H H4-OCH₃ NH H H 4-OCH₃ O H H 4-OCF₂H NH H H 4-OCF₂H O H H 4-Me NH H H 4-MeO H H 4-OCH₂CF₃ NH Me H 4-CF₃ NH H H 3,5-di-Me NH Me Me 4-CF₃ NH Me Me4-CF₃ O Et H 4-CF₃ NH n-Bu n-Bu 4-CF₃ NH CO₂Me H 4-CF₃ NH CO₂Me Me 4-CF₃NH CO₂Me n-Bu 4-CF₃ NH H H 3,4,5-tri-Me NH H H 3,4,5-tri-OMe NH H H6-CF₃ NH H H 6-F NH i-Pr H 4-CF₃ NH H H 6-Ph NH H H 6-Ph O H H4-O(Ph-4′-Cl) NH H H 4-(Ph-4′-Cl) NH L is C(O)CH₃, and n is 2. R¹ R²(R⁵)_(m) A H H — NH H H — O Me H — NH Me H — O Me Me — NH Me Me — O Et H— NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NH CO₂Me n-Bu — NH H H 4-FNH H H 4-F O H H 4-Cl NH H H 4-Cl O H H 4-Br NH H H 4-Br O H H 4-I NH HH 4-I O H H 4-CF₃ NH H H 4-CF₃ O H H 4-Ph NH H H 4-OPh NH H H 6-OPh NH HH 4-O(Ph-2′-Me) NH H H 4-OCH₃ NH H H 4-OCH₃ O H H 4-OCF₂H NH H H 4-OCF₂HO H H 4-Me NH H H 4-Me O H H 4-OCH₂CF₃ NH Me H 4-CF₃ NH H H 3,5-di-Me NHMe Me 4-CF₃ NH Me Me 4-CF₃ O Et H 4-CF₃ NH n-Bu n-Bu 4-CF₃ NH CO₂Me H4-CF₃ NH CO₂Me Me 4-CF₃ NH CO₂Me n-Bu 4-CF₃ NH H H 3,4,5-tri-Me NH H H3,4,5-tri-OMe NH H H 6-CF₃ NH H H 6-F NH i-Pr H 4-CF₃ NH H H 6-Ph NH H H6-Ph O H H 4-O(Ph-4′-Cl) NH H H 4-(Ph-4′-Cl) NH

TABLE 2B

L is H, and n is 0. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH Me H — OMe Me — NH Et H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NH H H 4-FNH H H 4-F O H H 4-Cl NH H H 4-Br NH H H 4-CF₃ NH H H 4-OCH₃ NH H H4-OCF₂H NH H H 4-Me NH H H 8-CH₃ NH Me H 4-CF₃ NH H H 3,5-di-Me NH Me Me4-CF₃ NH Me Me 4-CF₃ O Et H 4-CF₃ NH n-Bu n-Bu 4-CF₃ NH CO₂Me H 4-CF₃ NHH H 6-CF₃ NH H H 6-F NH i-Pr H 4-CF₃ NH L is C(O)CH₃, and n is 0. R¹ R²(R⁵)_(m) A H H — NH H H — O Me H — NH Me H — O Me Me — NH Et H — NH n-Bun-Bu — NH CO₂Me H — NH CO₂Me Me — NH H H 4-F NH H H 4-F O H H 4-Cl NH HH 4-Br NH H H 4-CF₃ NH H H 4-OCH₃ NH H H 4-OCF₂H NH H H 4-Me NH H H8-CH₃ NH Me H 4-CF₃ NH H H 3,5-di-Me NH Me Me 4-CF₃ NH Me Me 4-CF₃ O EtH 4-CF₃ NH n-Bu n-Bu 4-CF₃ NH CO₂Me H 4-CF₃ NH H H 6-CF₃ NH H H 6-F NHi-Pr H 4-CF₃ NH

TABLE 2C

L is H, and n is 0. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH Me H — OMe Me — NH Et H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NH H H 4-FNH H H 4-F O H H 4-Cl NH H H 4-Br NH H H 4-CF₃ NH H H 4-OCH₃ NH H H4-OCF₂H NH H H 4-Me NH H H 4-OCH₂CF₃ NH Me H 4-CF₃ NH H H 3,5-di-Me NHMe Me 4-CF₃ NH Me Me 4-CF₃ O Et H 4-CF₃ NH n-Bu n-Bu 4-CF₃ NH CO₂Me H4-CF₃ NH i-Pr H 4-CF₃ NH L is C(O)CH₃, and n is 0. R¹ R² (R⁵)_(m) A H H— NH H H — O Me H — NH Me H — O Me Me — NH Et H — NH n-Bu n-Bu — NHCO₂Me H — NH CO₂Me Me — NH H H 4-F NH H H 4-F O H H 4-Cl NH H H 4-Br NHH H 4-CF₃ NH H H 4-OCH₃ NH H H 4-OCF₂H NH H H 4-Me NH H H 4-OCH₂CF₃ NHMe H 4-CF₃ NH H H 3,5-di-Me NH Me Me 4-CF₃ NH Me Me 4-CF₃ O Et H 4-CF₃NH n-Bu n-Bu 4-CF₃ NH CO₂Me H 4-CF₃ NH i-Pr H 4-CF₃ NH

TABLE 2D

L is H, and n is 0. R¹ R² (R⁵)_(m) A H H — NH H H — O Me H — NH Me H — OMe Me — NH Et H — NH n-Bu n-Bu — NH CO₂Me H — NH CO₂Me Me — NH H H 6-FNH H H 6-F O H H 6-Cl NH H H 6-Br NH H H 6-CF₃ NH H H 6-OCH₃ NH H H6-OCF₂H NH H H 6-Me NH H H 6-OCH₂CF₃ NH Me H 6-CF₃ NH H H 3,5-di-Me NHMe Me 6-CF₃ NH Me Me 6-CF₃ O Et H 6-CF₃ NH n-Bu n-Bu 6-CF₃ NH CO₂Me H6-CF₃ NH i-Pr H 6-CF₃ NH L is C(O)CH₃, and n is 0. R¹ R² (R⁵)_(m) A H H— NH H H — O Me H — NH Me H — O Me Me — NH Et H — NH n-Bu n-Bu — NHCO₂Me H — NH CO₂Me Me — NH H H 6-F NH H H 6-F O H H 6-Cl NH H H 6-Br NHH H 6-CF₃ NH H H 6-OCH₃ NH H H 6-OCF₂H NH H H 6-Me NH H H 6-OCH₂CF₃ NHMe H 6-CF₃ NH H H 3,5-di-Me NH Me Me 6-CF₃ NH Me Me 6-CF₃ O Et H 6-CF₃NH n-Bu n-Bu 6-CF₃ NH CO₂Me H 6-CF₃ NH i-Pr H 6-CF₃ NH

TABLE 3A

R¹ R² (R⁵)_(m) H H — Me H — Me Me — Et H — n-Bu n-Bu — CO₂Me H — CO₂MeMe — CO₂Me n-Bu — H H 4-F H H 4-Cl H H 4-Br H H 4-I H H 4-CF₃ (Ex. 2,Step 1) H H 4-OCH₃ H H 4-OCF₂H H H 4-Ph H H 4-OPh H H 6-OPh H H4-O(Ph-2′-Me) H H 4-Me H H 4-OCH₂CF₃ Me H 4-CF₃ H H 3,5-di-Me Me Me4-CF₃ Et H 4-CF₃ n-Bu n-Bu 4-CF₃ CO₂Me H 4-CF₃ CO₂Me Me 4-CF₃ CO₂Me n-Bu4-CF₃ H H 3,4,5-tri-Me H H 3,4,5-tri-OMe H H 6-CF₃ H H 6-F i-Pr H 4-CF₃H H 6-Ph H H 4-O(Ph-4′-Cl) H H 4-(Ph-4′-Cl)

TABLE 3B

R¹ R² (R⁵)_(m) H H — Me H — Me Me — Et H — n-Bu n-Bu — CO₂Me H — CO₂MeMe — H H 4-F H H 4-Cl H H 4-Br H H 4-CF₃ H H 4-OCH₃ H H 4-OCF₂H H H 4-MeH H 8-CH₃ Me H 4-CF₃ H H 3,5-di-Me Me Me 4-CF₃ Et H 4-CF₃ n-Bu n-Bu4-CF₃ CO₂Me H 4-CF₃ H H 6-CF₃ H H 6-F i-Pr H 4-CF₃

TABLE 3C

R¹ R² (R⁵)_(m) H H — Me H — Me Me — Et H — n-Bu n-Bu — CO₂Me H — CO₂MeMe — H H 4-F H H 4-Cl H H 4-Br H H 4-CF₃ H H 4-OCH₃ H H 4-OCF₂H H H 4-MeH H 4-OCH₂CF₃ Me H 4-CF₃ H H 3,5-di-Me Me Me 4-CF₃ Et H 4-CF₃ n-Bu n-Bu4-CF₃ CO₂Me H 4-CF₃ i-Pr H 4-CF₃

TABLE 3D

R¹ R² (R⁵)_(m) H H — Me H — Me Me — Et H — n-Bu n-Bu — CO₂Me H — CO₂MeMe — H H 6-F H H 6-Cl H H 6-Br H H 6-CF₃ H H 6-OCH₃ H H 6-OCF₂H H H 6-MeH H 6-OCH₂CF₃ Me H 6-CF₃ H H 3,5-di-Me Me Me 6-CF₃ Et H 6-CF₃ n-Bu n-Bu6-CF₃ CO₂Me H 6-CF₃ i-Pr H 6-CF₃

1. A method for preparing a compound of Formula V

wherein K is, together with the two contiguous linking carbon atoms, aphenyl ring, a 5- or 6-membered heteroaromatic ring or an aromatic 8-,9- or 10-membered fused carbobicyclic or heterobicyclic ring systemwherein each ring or ring system is optionally substituted; R¹ is H, C₁to C₄ alkyl or CO₂R³; R² is H or C₁ to C₄ alkyl; R³ is C₁ to C₄ alkyl;and R⁴ is CHR¹R²; the method comprising contacting a compound of FormulaIII,

 wherein A is NH and K is as defined for Formula V, with a compound ofFormula IVR¹R²CHS(O)R⁴  IV  wherein R⁴ is CHR¹R² and R¹ and R² are as defined forFormula V, in dichloromethane as an inert solvent and in the presence ofsulfur trioxide as an activating agent to form a reaction product, andwashing the reaction product in the inert solvent with an aqueoussolution of a base to form the compound of Formula V.
 2. The method ofclaim 1 wherein the base is selected from an alkali metal carbonate,hydroxide or phosphate.
 3. The method of claim 1 wherein the amount ofsulfur trioxide is about 1.8 to 2.2 equivalents relative to the amountof the compound of Formula III.
 4. The method of claim 3 wherein theamount of sulfur trioxide is about 1.9 to 2.1 equivalents relative tothe amount of the compound of Formula III.
 5. The method of claim 1wherein the amount of the compound of Formula IV is about 0.5 to 3equivalents relative to the amount of sulfur trioxide.
 6. The method ofclaim 5 wherein the amount of the compound of Formula IV is about 1 to 2equivalents relative to the amount of sulfur trioxide.
 7. The method ofany of claims 1 through 6 wherein R¹ is H or CO₂CH₃, R² is H, and R⁴ isCH₃ or CH₂CO₂CH₃.
 8. The method of claim 7 wherein R¹ is H, R² is H andR⁴ is CH₃.
 9. The method of any of claims 1 through 6 wherein K,together with the two contiguous carbon atoms, is a phenyl ringoptionally substituted with one or more groups independently selectedfrom halogen, C₁–C₄ alkyl, C₁–C₄ alkoxy, C₁–C₄ haloalkyl, C₁–C₄haloalkoxy, phenyl and phenoxy, each phenyl or phenoxy group optionallysubstituted with one or more groups independently selected from halogen,C₁–C₄ alkyl, C₁–C₄ alkoxy, C₁–C₄ haloalkyl and C₁–C₄ haloalkoxy.